rs147700427

Variant names:

• chr17-44007690-C-G
• rs147700427
• NM_153006.3:c.1368C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-44007690-C-G
• chr17-44007690-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_153006.3(NAGS):​c.1368C>G​(p.Ser456Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,604,718 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S456S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: NAGS NM_153006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.48
• Publications: 1 publications found

Genes affected

NAGS (HGNC:17996): (N-acetylglutamate synthase) The N-acetylglutamate synthase gene encodes a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG) from glutamate and acetyl coenzyme-A. NAG is a cofactor of carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle in mammals. This gene may regulate ureagenesis by altering NAG availability and, thereby, CPSI activity. Deficiencies in N-acetylglutamate synthase have been associated with hyperammonemia. [provided by RefSeq, Jul 2008]

NAGS Gene-Disease associations (from GenCC):

• hyperammonemia due to N-acetylglutamate synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 17-44007690-C-G is Benign according to our data. Variant chr17-44007690-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 384582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00182 (277/152296) while in subpopulation NFE AF = 0.00297 (202/68024). AF 95% confidence interval is 0.00263. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	NM_153006.3	MANE Select	c.1368C>G	p.Ser456Ser	synonymous	Exon 6 of 7	NP_694551.1	Q8N159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGS	ENST00000293404.8	TSL:1 MANE Select	c.1368C>G	p.Ser456Ser	synonymous	Exon 6 of 7	ENSP00000293404.2	Q8N159
	NAGS	ENST00000906978.1		c.1383C>G	p.Ser461Ser	synonymous	Exon 6 of 7	ENSP00000577037.1
	NAGS	ENST00000589767.1	TSL:2	c.1299C>G	p.Ser433Ser	synonymous	Exon 6 of 7	ENSP00000465408.1	K7EK11

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00170 AC: 393 AN: 231746 AF XY: 0.00164

Gnomad AFR exome AF: 0.000422

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00282 AC: 4090 AN: 1452422 Hom.: 13 Cov.: 30 AF XY: 0.00271 AC XY: 1955 AN XY: 721544

African (AFR) AF: 0.000451 AC: 15 AN: 33248

American (AMR) AF: 0.00134 AC: 59 AN: 43900

Ashkenazi Jewish (ASJ) AF: 0.000851 AC: 22 AN: 25848

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39202

South Asian (SAS) AF: 0.000663 AC: 56 AN: 84466

European-Finnish (FIN) AF: 0.000495 AC: 26 AN: 52558

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5758

European-Non Finnish (NFE) AF: 0.00336 AC: 3723 AN: 1107436

Other (OTH) AF: 0.00282 AC: 169 AN: 60006

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74468

African (AFR) AF: 0.000578 AC: 24 AN: 41554

American (AMR) AF: 0.00229 AC: 35 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00181

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperammonemia, type III (3)
-	-	2	not provided (2)
-	-	1	NAGS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.7
DANN	Benign	0.79
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147700427; hg19: chr17-42085058;